title: Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation.
abstract: Dexamethasone (Dex)-induced osteoporosis has been described as the most severe side effect in long-term glucocorticoid therapy. The decreased bone mass and the increased marrow fat suggest that Dex possibly shifts the differentiation of bone marrow stromal cells (BMSCs) to favor adipocyte over osteoblast, but the underlying mechanisms are still unknown. In this paper, we established a Dex-induced osteoporotic mouse model, and found that BMSCs from Dex-treated mice are more likely to differentiate into adipocyte than those from control mice, even under the induction of bone morphogenetic protein-2 (BMP2). We also discovered both in vitro and in vivo that the expression level of adipocyte regulator CCAAT/enhancer-binding protein alpha (C/EBPalpha) is significantly upregulated in Dex-induced osteoporotic BMSCs during osteoblastogenesis by a mechanism that involves inhibited DNA hypermethylation of its promoter. Knockdown of C/EBPalpha in Dex-induced osteoporotic cells rescues their differentiation potential, suggesting that Dex shifts BMSC differentiation by inhibiting C/EBPalpha promoter methylation and upregulating its expression level. We further found that the Wnt/beta-catenin pathway is involved in Dex-induced osteoporosis and C/EBPalpha promoter methylation, and its activation by LiCl rescues the effect of Dex on C/EBPalpha promoter methylation and osteoblast/adipocyte balance. This study revealed the C/EBPalpha promoter methylation mechanism and evaluated the function of Wnt/beta-catenin pathway in Dex-induced osteoporosis, providing a useful therapeutic target for this type of osteoporosis.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai Jiao Tong University School of Medicine (SJTUSM), China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: N
authors.initials: N
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: J C
authors.initials: JC
authors.lastname: Fernandes
authors.forename: K
authors.initials: K
authors.lastname: Dai
authors.forename: X
authors.initials: X
authors.lastname: Zhang
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics
chemical_list: D055396:Bone Morphogenetic Protein 2; D022763:CCAAT-Enhancer-Binding Protein-alpha; D003907:Dexamethasone; D018021:Lithium Chloride